Anorexia-cachexia occurs because detection of energy deficit by the brain becomes impaired due to cytokine excess. The arcuate neuropeptide Y (NPY) neurons normally activate anabolic processes during energy deficit in order to restore energy homeostasis. Approximately 40% of NPY neurons are also glucose-inhibited neurons (NPY-GI). Recent work from our laboratory shows that fasting increases cfos activation in NPY neurons. Fasting also increases NPY release in response to decreased glucose, in part by sensitizing NPY-GI neurons to decreased glucose. This is mediated by AMP-activated protein kinase (AMPK). This proposal is designed to study the role of NPY-GI neurons in the development of disease related anorexia-cachexia. NPY neurocircuitry is dysfunctional during anorexia-cachexia. The endotoxin, lipopolysaccharide (LPS), causes anorexia and prevents fasting-induced increases in arcuate cfos activation. The central effects of LPS on anorexia are mediated, in part, by the inflammatory cytokine, tumor necrosis factor alpha (TNFalpha). TNFalpha inhibits AMPK in skeletal muscle. We hypothesize that increased levels of TNFalpha during anorexia-cachexia blunt the ability of NPY-GI neurons to respond to decreased glucose due to AMPK suppression. This hypothesis will be tested by 2 specific aims. Specific Aim 1 will determine whether an anorectic dose of LPS blocks fasting-induced changes in NPY-GI neurons. Specific Aim 2 will determine whether TNFalpha blunts the response of NPY-GI neurons to decreased glucose via AMPK suppression. Specific Aim 2 will also evaluate signaling pathways which may normalize glucose sensitivity in NPY-GI neurons. Very little is known regarding the cellular mechanisms underlying central dysfunction in anorexia-cachexia, yet this syndrome is responsible for >20% of patients deaths in chronic diseases such as cancer, AIDS and cardiac failure. The studies proposed herein will provide a clear framework on which to understand how NPY-GI neurons become impaired during anorexia-cachexia. These studies will lead to the development of therapies for disease related anorexia-cachexia which will significantly improve survival during a number of chronic diseases. PUBLIC HEALTH RELEVANCE: We hypothesize that normal fasting-induced changes in NPY neurons are blocked during anorexia-cachexia leading to impaired activation of anabolic processes and life- threatening wasting. This occurs, in part, because the inflammatory cytokine, tumor necrosis factor alpha (TNF), blunts the ability of NPY neurons to sense glucose decreases via suppression of AMP-activated protein kinase (AMPK).